1. Field of the Invention
The invention relates to a compound and a method of preparing the same, and more particularly to 5,6-dimethyl xanthone-4-acetic acid (DMXAA) derivatives and its preparation method, as well as its use as anticancer and antibacterial drugs.
2. Description of the Related Art
DMXAA is a tumor angiogenesis inhibitor and used for the treatment of cancers. Nowadays, it has been applying in the clinical trial phase III. Rewcastle et al. disclosed a method of preparation of DMXAA, as shown in Scheme 1 (Rewcastle et al.; J. Med. Chem. 1991, 34, 217).

The starting material of 2,3-dimethyl aniline (1) was mixed and condensed with hydroxylamine and chloral hydrate to yield isonitrosoacetanilide (2), then to yield isatin (3) by acid-catalyzed cyclization and 2-amino-3,4-dimethyl-benzoic acid (4) by an oxidative ring cleavage reaction. The total yield of the first three steps was 37%. The steps involved in hydroxylamine and chloral hydrate, both of which were toxic. Additionally, the steps were a multi-phase reaction, requiring careful control on the reaction time and temperature. Under carefully-controlled conditions, 2-amino-3,4-dimethyl-benzoic acid (4) was diazotized to yield an iodide (5). The iodide was condensed with 2-hydroxyphenylacetic acid to yield 2-[2-(carboxymethyl)phenoxy]-3,4-dimethyl-benzoic acid (6), which was further cyclized to yield DMXAA. The total yield of the six steps was about 12%.
Atwell et al. disclosed another method of preparation of the key intermediate of 2-amino-3,4-dimethyl-benzoic acid (4) (Atwell et al.; Eur. J. Med. Chem., 2002, 37, 825), as shown in Scheme 2.

3,4-dimethyl-benzoic acid was directly nitrified and condensed to yield a mixture consisting of nitro isomers 9a, 9b, and 9c. The ratio of 9a to 9b to 9c was 1:8:2. The mixture was recrystallized from acetic acid to remove 9a, and the ratio of the remaining 9b to 9c was 3.4:1. After catalytic hydrogenation, the remaining mixture was transformed into a sodium salt solution, which was further neutralized with acetic acid to give a pure crystal of 2-amino-3,4-dimethyl-benzoic acid (4) (the purity was 96%; the total yield was 42%). An improved method of preparation of DMXAA was also disclosed in the above-mentioned literature. Compared with Scheme 1 (32%), Scheme 2 had a higher yield of 2-amino-3,4-dimethyl-benzoic acid (4). However, step-by-step recrystallization limited the industrial production of DMXAA.
Rewcastle et al. taught a method of improving the first step of preparation of DMXAA, i.e., from the starting material of 2,3-dimethyl aniline (1) to isonitrosoacetanilide (2) (Rewcastle et al., Tet. Lett., 2005, 46, 8719), as shown in Scheme 3.

2,3-dimethyl aniline was acylated with 2,2-diacetoxyacetyl chloride to give a crude product of diacetate (1a). The crude product was contacted with hydroxylamine to give isonitrosoacetanilide (2).
Compared with Scheme 1 (Rewcastle et al.; J. Med. Chem. 1991, 34, 217) where the reaction was non-homogeneous and the yield was 54%, the reaction in Scheme 3 was homogeneous and the yield was 83%.
However, all the above-mentioned methods have disadvantages such as complicated process, low yield, serious pollution, and difficulty for industrial production.